The matrix metalloproteases (aka. matrix metalloendo-proteinases or MMPs) are a family of zinc endoproteinases which include, but are not limited to, interstitial collagenase (aka. MMP-1), stromelysin (aka. proteoglycanase, transin, or MMP-3), gelatinase A (aka. 72 kDa-gelatinase or MMP-2) and gelatinase B (aka. 95 kDa-gelatinase or MMP-9). These MMPs are secreted by a variety of cells including fibroblasts and chondrocytes, along with natural proteinatious inhibitors known as TIMPs (Tissue Inhibitor of MetalloProteinase).
All of these MMPs are capable of destroying a variety of connective tissue components of articular cartilage or basement membranes. Each MMP is secreted as an inactive proenzyme which must be cleaved in a subsequent step before it is able to exert its own proteolytic activity. In addition to the matrix destroying effect, certain of these MMPs such as MMP-3 have been implemented as the in vivo activator for other MMPs such as MMP-1 and MMP-9 (A. Ho, H. Nagase, Arch Biochem Biophys., 267, 211-16 (1988); Y. Ogata, J. J. Enghild, H. Nagase, J. Biol. Chem., 267, 3581-84 (1992)). Thus, a cascade of proteolytic activity can be initiated by an excess of MMP-3. It follows that specific MMP-3 inhibitors should limit the activity of other MMPs that are not directly inhibited by such inhibitors.
It has also been reported that MMP-3 can cleave and thereby inactivate the endogenous inhibitors of other proteinases such as elastase (P. G. Winyard, Z. Zhang, K. Chidwick, D. R. Blake, R. W. Carrell G., Murphy, FEBS Letts., 279, 1, 91-94 (1991)). Inhibitors of MMP-3 could thus influence the activity of other destructive proteinases by modifying the level of their endogenous inhibitors.
MMP inhibitors may also be useful in the inhibition of other mammalian metalloproteases such as the adamalysin family (or ADAMs) whose members include TNF.alpha. converting enzyme (TACE) and ADAM-10, which can cause the release of TNF from cells.
A number of diseases or conditions are thought to be mediated by excess or undesired matrix-destroying metalloprotease activity or by an imbalance in the ratio of the MMPs to the TIMPs or through the action of the release of TNF. These include: a) osteoarthritis (Woessner, et al., J. Biochelogical Chem 1984., 259(6), 3633-3638; J. Rheumatol. 1983, 10, 852-860; M. Zafarullah, et al., J. Rheumatol. 1993, 20, 693-697; H. J. Andrews, et al., Agents Actions 1992, 37, 147-154; A. J. Ellis, et al., Biochem. Biophys. Res. Commun. 1994, 201, 94-101), b) rheumatic diseases and conditions such as autoimmune disease, rheumatoid arthritis (D. E. Mullins, et al., Biochim. Biophys. Acta 1983, 695, 117-214; Arthritis and Rheumatism 1977, 20, 1231-1239; Arthritis and Rheumatism 1991, 34, 1076-1105; Maini. J. Royal Coll. Physicians London 1996, 30, 344), c) septic arthritis (R. J. Williams, et al., Arthr. Rheum. 1990, 33, 533-41), d) cancer including tumor growth, tumor metastasis and angiogenesis (R. Reich, et al., Cancer Res. 1988, 48, 3307-3312; MucWierzgon et al. J. Biol. Regulators Homeostatic Agents 1996, 10, 25; Levy et al. Crit. Rev. Immunol. 1996,16, 31; G. Taraboletti, et al., J. Nat. Cancer Institute 1995, 87, 293; R. Benelli, et al., Oncology Research 1994, 6, 251-257; and L M. Matrisian, et al., Proc. Nat'l. Acad. Sci. 1986, USA, 83, 9413-7; Y. A. DeClerck, et al., Cancer Res. 1992, 52, 701-708; A. Y. Strongin, et al., J. Biol. Chem. 1993, 268, 14033-14039; A. Melchiori, et al., Cancer Res. 1992, 52, 2353-2356; Davies, et al., Cancer Res. 1993, 53, 2087-2091; W. L. Monsky, et al., Cancer Res. 1993, 53, 3159-3164), e) periodontal diseases (C. M. Overall, et al., J. Periodontal Res. 1987, 22, 81-88), f) corneal ulceration (F. R. Burns, et al., Invest. Opthalmol. 1989, 30, 1569-1575), g) proteinuria (W. H. Baricos, et al., Biochem. J. 1988, 254, 609-612), h) various cardiovascular and pulmonary diseases such as atherosclerosis (A. M. Henney, et al., Proc. Nat'l. Acad. Sci. USA 1991, 88, 8154-8158), thrombotic events (Sawicki, et al. Nature 1997, 386, 616-619), atheroma, hemodynamic shock, unstable angina, restenosis, heart failure, i) aneurysmal diseases including those of the aorta, heart or brain (N. Vine and J. T. Powell, Clin. Sci. 1991, 81, 233-9), j) birth control (J. F. Woessner, et al., Steroids 1989, 54, 491-499), k) dystrophobic epidermolysis bullosa (A. Kronberger, et al., J. Invest. Dermatol. 1982, 79, 208-211), l) degenerative cartilage loss following traumatic joint injury (L. A. Walakovits, et al., Arthritis Rheum. 1992, 35, 35-42), m) osteopenias and other diseases of abnormal bone loss including osteoporosis (Pacifici et al. J. Bone Mineral Res. 1996, 11, 1043), n) tempero mandibular joint disease, o) pulmonary diseases such as chronic obstructive pulmonary disease, p) demyelinating diseases of the nervous system such as multiple sclerosis (M. S.; Coyle. Adv. Neuroimmunol. 1996, 6, 143; Matusevicius et al. J. Neuroimmunol. 1996, 66, 115); Brosnan et al. Brain Pathol. 1996, 6,243 and J. Neurochem. 1988, 50, 688-694; R. Martin and H. F. McFarland, Crit. Rev. Clin. Lab. Sci. 1995, 32, 121-182), q) metabolic diseases including diabetes and obesity mediated by insulin resistance (Stephens et al. J. Biol. Chem. 1997, 272, 971; Ofei et al. Diabetes 1996, 45, 881), macular degeneration and diabetic retinopathy mediated by agiogenesis, cachexia, premature skin aging (G. J. Fisher, et al., New Eng. J. Med. 1997, 337, 1419-1428), r) impaired wound healing including burns, s) decubital ulcers, t) acute and chronic neurodegenerative disorders (E. G. McGeer and P. L. McGeer, in D. B. Calne, ed. Neuodegenerative Diseases, W. B. Saunders 1994, 277-300; N. J. Rothwell and J. K. Relton, Neurosci. Biobehav. Rerv. 1993, 17, 217-227; W. Y. Voon, et al., Trends Neurosci. 1998, 21 (2), 75-80) including stroke (R. K. Clark, et al., Brain Res. Bull. 1993, 31, 565-572; D. Goulian and K. Vaca, Stroke 1993, 24 (Suppl 12), 184-190), spinal cord and traumatic brain injury (R. Martin, et al., Annul Rev. Immunol. 1992, 10, 153-187), amyotrophic lateral sclerosis, cerebral amyloid angiopathy (T. I. Mandybur and G. Balko, Clin. Neuopharm. 1992, 15, 241-247), CNS injuries in AIDS (H. E. Gendelman and M. Tardieu, J. Leukocyte Biol. 1994, 56, 387-388), Parkinson's disease, Alzheimer's disease (P. H. Patterson, Cur. Opinion Neurobiol. 1995, 5, 642-646; P. L. McGeer, et al., Alzheimers Dis. Assoc. Disorders 1994, 8, 149-158; J. Rogers, et al., Neurobiology of Aging 1996, 17, 681-686), Huntington's diseases, prion diseases, myasthenic gravis, and Duchenne's muscular dystrophy, u) pain, v) autoimmune encephalomyelitis (Gijbels, et al., J. Clin. Invest. 1994, 94, 2177-2182; A. M. Ramanic, et al., J. Cell Biology 1994, 125, 1165-1178) and w) diseases linked to TNFa production and/or signaling such as a wide variety of inflammatory and/or immunomodulatory diseases, including acute rheumatic fever (Yegin et al. Lancet 1997, 349, 170), bone resorption (Pacifici et al. J. Clin. Endocrinol. Metabol. 1997, 82, 29), sepsis (Blackwell et al. Br. J. Anaesth. 1996, 77, 110), gram negative sepsis (Debets et al. Prog. Clin. Biol. Res. 1989, 308, 463), septic shock (Tracey et al. Nature 1987, 330, 662; Girardin et al. New England J. Med. 1988, 319, 397), endotoxic shock (Beutler et al. Science 1985, 229, 869; Ashkenasi et al. Proc. Nat'l. Acad. Sci. USA 1991, 88, 10535), toxic shock syndrome, (Saha et al. J. Immunol. 1996, 157, 3869; Lina et al. FEMS Immunol. Med. Microbiol. 1996, 13, 81), systemic inflammatory response syndrome (Anon. Crit. Care Med. 1992, 20, 864), inflammatory bowel diseases (Stokkers et al. J. Inflamm. 1995-6, 47, 97) including Crohn's disease (van Deventer et al. Aliment. Pharmacol. Therapeu. 1996, 10 (Suppl. 2), 107; van Dullemen et al. Gastroenterology 1995, 109, 129) and ulcerative colitis (Masuda et al. J. Clin. Lab. Immunol. 1995, 46, 111), Jarisch-Herxheimer reactions (Fekade et al. New England J. Med. 1996, 335, 311), asthma (Amrani et al. Rev. Malad. Respir. 1996, 13, 539), adult respiratory distress syndrome (Roten et al. Am. Rev. Respir. Dis. 1991, 143, 590; Suter et al. Am. Rev. Respir. Dis. 1992, 145, 1016), acute pulmonary fibrotic diseases (Pan et al. Pathol. Int. 1996, 46, 91), pulmonary sarcoidosis (Ishioka et al. Sarcoidosis Vasculitis Diffuse Lung Dis. 1996, 13, 139), allergic respiratory diseases (Casale et al. Am. J. Respir. Cell Mol. Biol. 1996, 15, 35), silicosis (Gossart et al. J. Immunol. 1996, 156, 1540; Vanhee et al. Eur. Respir. J. 1995, 8, 834), coal worker's pneumoconiosis (Borm et al. Am. Rev. Respir. Dis. 1988, 138, 1589), alveolar injury (Horinouchi et al. Am. J. Respir. Cell Mol. Biol. 1996, 14, 1044), hepatic failure (Gantner et al. J. Pharmacol. Exp. Therap. 1997, 280, 53), liver disease during acute inflammation (Kim et al. J. Biol. Chem. 1997, 272, 1402), severe alcoholic hepatitis (Bird et al. Ann. Intern. Med. 1990, 112, 917), malaria (Grau et al. Immunol. Rev. 1989, 112, 49; Taverne et al. Parasitol. Today 1996, 12, 290) including Plasmodium falciparum malaria (Perlmann et al. Infect. Immunit. 1997, 65, 116) and cerebral malaria (Rudin et al. Am. J. Pathol. 1997, 150, 257), congestive heart failure (Doyama et al. Int. J. Cardiol. 1996, 54, 217; McMurray et al. Br. Heart J. 1991, 66, 356), damage following heart disease (Malkiel et al. Mol. Med. Today 1996, 2, 336), arteriosclerosis including atherosclerosis (Parums et al. J. Pathol. 1996, 179, A46), Alzheimer's disease (Fagarasan et al. Brain Res. 1996, 723, 231; Aisen et al. Gerontology 1997, 43, 143), acute encephalitis (Ichiyama et al. J. Neurol. 1996, 243, 457), brain injury (Cannon et al. Crit. Care Med. 1992, 20, 1414; Hansbrough et al. Surg. Clin. N. Am. 1987, 67, 69; Marano et al. Surg. Gynecol. Obstetr. 1990, 170, 32), pancreatitis (Exley et al. Gut 1992, 33, 1126) including systemic complications in acute pancreatitis (McKay et al. Br. J. Surg. 1996, 83, 919), impaired wound healing in infection inflammation and cancer (Buck et al. Am. J. Pathol. 1996, 149, 195), myelodysplastic syndromes (Raza et al. Int. J. Hematol. 1996, 63, 265), systemic lupus erythematosus (Maury et al. Arthritis Rheum. 1989, 32, 146), biliary cirrhosis (Miller et al. Am. J. Gasteroenterolog. 1992, 87, 465), bowel necrosis (Sun et al. J. Clin. Invest. 1988, 81, 1328), psoriasis (Christophers. Austr. J. Dermatol. 1996, 37, S4), radiation injury (Redlich et al. J. Immunol. 1996, 157, 1705), and toxicity following administration of monoclonal antibodies such as OKT3 (Brod et al. Neurology 1996, 46, 1633), host-versus-graft reactions (Piguet et al. Immunol. Ser. 1992, 56, 409) including ischemia reperfusion injury (Colletti et al. J. Clin. Invest. 1989, 85, 1333) and allograft rejections including those of the kidney (Maury et al. J. Exp. Med. 1987, 166, 1132), liver (Imagawa et al. Transplantation 1990, 50, 219), heart (Bolling et al. Transplantation 1992, 53, 283), and skin (Stevens et al. Transplant. Proc. 1990, 22, 1924), lung allograft rejection (Grossman et al. Immunol. Allergy Clin. N. Am. 1989, 9, 153) including chronic lung allograft rejection (obliterative bronchitis; LoCicero et al. J. Thorac. Cardiovasc. Surg. 1990, 99, 1059), as well as complications due to total hip replacement (Cirino et al. Life Sci. 1996, 59, 86), infectious diseases (review: Beutler et al. Crit. Care Med. 1993, 21, 5423; Degre. Biotherapy 1996, 8, 219) including tuberculosis (Rook et al. Med. Malad. Infect. 1996, 26, 904), Helicobacter pylori infection during peptic ulcer disease (Beales et al. Gastroenterology 1997, 112, 136), Chaga's disease resulting from Trypanosoma cruzi infection (Chandrasekar et al. Biochem. Biophys. Res. Commun. 1996, 223, 365), effects of Shiga-like toxin resulting from E. coli infection (Harel et al. J. Clin. Invest. 1992, 56, 40), the effects of enterotoxin A resulting from Staphylococcus infection (Fischer et al. J. Immunol. 1990, 144, 4663), meningococcal infection (Waage et al. Lancet 1987, 355; Ossege et al. J. Neurolog. Sci. 1996, 144, 1), and infections from Borrelia burgdorferi (Brandt et al. Infect. Immunol. 1990, 58, 983), Treponema pallidum (Chamberlin et al. Infect. Immunol. 1989, 57, 2872), cytomegalovirus (CMV; Geist et al. Am. J. Respir. Cell Mol. Biol. 1997, 16, 31), influenza virus (Beutler et al. Clin. Res. 1986, 34, 491a), Sendai virus (Goldfield et al. Proc. Nat'l. Acad. Sci. USA 1989, 87, 1490), Theiler's encephalomyelitis virus (Sierra et al. Immunology 1993, 78, 399), and the human immunodeficiency virus (HIV; Poli. Proc. Nat'l. Acad. Sci. USA 1990, 87, 782; Vyakaram et al. AIDS 1990, 4, 21; Badley et al. J. Exp. Med. 1997, 185, 55).
The need for new therapies is especially important in the case of arthritic diseases. The primary disabling effect of oeteoarthritis (OA), rheumatoid arthritis (RA) and septic arthritis is the progressive loss of articular cartilage and thereby normal joint function. No marketed pharmaceutical agent is able to prevent or slow this cartilage loss, although nonsteroidal antiinflammatory drugs (NSAIDs) have been given to control pain and swelling. The end result of these diseases is total loss of joint function which is only treatable by joint replacement surgery. MMP inhibitors are expected to halt or reverse the progression of cartilage loss and obviate or delay surgical intervention.
Proteases are critical elements at several stages in the progression of metastatic cancer. In this process, the proteolytic degradation of structural protein in the basal membrane allows for expansion of a tumor in the primary site, evasion from this site as well as homing and invasion in distant, secondary sites. Also, tumor induced angiogenesis is required for tumor growth and is dependent on proteolytic tissue remodeling. Transfection experiments with various types of proteases have shown that the matrix metalloproteases play a dominant role in these processes in particular gelatinases A and B (MMP-2 and MMP-9, respectively). For an overview of this field see Biochimica et Biophysica Acta 695 (1983), 177-214; Eur. Respir. J. 7 (1994), 2062-2072; Critical Reviews in Oral Biology and Medicine 4 (1993), 197-250.
Furthermore, it has been shown that inhibition of degradation of extracellular matrix by the native matrix metalloprotease inhibitor TIMP-2 (a protein) arrests cancer growth (Cancer Res. 52, 701-708, 1992) and that TIMP-2 inhibits tumor-induced angiogenesis in experimental systems (Science 248, 1408-1410, 1990). For a review see Annals of the New York Academy of Sciences 1994, 222-232. It was furthermore demonstrated that the synthetic matrix metalloprotease inhibitor batimastat when given intraperitoneally inhibits human colon tumor growth and spread in an orthotopic model in nude mice (Cancer Res. 54, 4726-4728, 1994) and prolongs the survival of mice bearing human ovarian carcinoma xenografts (Cancer Res. 53, 2087-2091, 1993). The use of this and related compounds has been described in WO-A-9321942.
There are a number of patents and patent applications claiming the use of metalloproteinase inhibitors for the retardation of metastatic cancer, promoting tumor regression, inhibiting cancer cell proliferation, slowing or preventing of cartilage loss associated with osteoarthritis or for treatment of other diseases as noted above (e.g. WO-A-9519965, WO-A-9519956, WO-A-9519957, WO-A-9519961, WO-A-9321942, WO-A-9321942, WO-9421625, U.S. Pat. Nos. 4,599,361; 5,190,937; EP 0574 758 A1, published Dec. 22, 1993; EP 026 436 A1 published Aug. 3, 1988; and EP 0520 573 A1, published Dec. 30, 1992). The preferred compounds of these patents have peptide backbones with a zinc complexing group (hydroxamic acid, thiol, carboxylic acid or phosphinic acid) at one end and a variety of side chains, both those found in the natural amino acids as well as those with more novel functional groups. Such small peptides are often poorly absorbed, exhibiting low oral bioavailability. They are also subject to rapid proteolytic metabolism, thus having short half lives. As an example, batimastat, the compound described in WO-A-9321942, can only be given intraperitoneally.
Some recent patents describe the use of hyroxamic acids with sulfonamide or sulfone moieties as backbones. See, for example WO 9807697, EP 818442 or WO 9749679 (representative structures shown below). ##STR4##
Matrix metalloprotease inhibitors which are derivatives of butyric and pentanoic acids are disclosed in the following published PCT applications: WO 96/15096, WO 97/43237, WO 97/43240, WO 97/43247, WO 97/43239, WO 97/43245, and WO 97/43238.